1. Field of the Invention
The present invention relates generally to anti-viral agents. More particularly, the present invention relates to pharmaceutical compositions that are generally characterized as safe, substantially non-irritating and of broad-spectrum antiviral activities.
2. Description of the Related Art
The upper respiratory tract (URT) and genitalia are the routes most often used by viruses that lead to viral infections. Viral infections in URT are best characterized by flu and common cold, and viral infections in genital areas are represented by herpes simplex infections, HIV infections, and other sexually transmitted diseases including hepatitis and those caused by Epstein-Barr viruses.
Until the advent of AIDS, flu or influenza virus was the last uncontrolled pandemic killer of humans. In the United States, influenza currently causes more morbidity and mortality than AIDS. For the 1990-1991 through 1998-1999 seasons, the greatest mean number of deaths was associated with influenza A virus, with annual mean (SD) of 8097 (3084) underlying pneumonia and influenza deaths (Thompson et al., JAMA 289:179-86, 2003).
Usually, the influenza viruses are a group of RNA viruses designated as types A, B, and C, with influenza A virus being the most virulent. This is because influenza A virus undergoes periodic antigenic shifts to evade the human immune systems and to promote widespread infection.
The influenza virus initially infects epithelial cells in the URT. It enters the host cells by a process of membrane fusion. This may occur at the cell plasma membrane or within the endocytic vacoular system. Upon binding to cell surface sialic acid residues on glycoproteins and glycolipids, the virus undergoes endocytosis via coated pits and vesicles and is then delivered to endosomes.
Four currently licensed agents are available in the United States for the systemic prophylaxis or treatment of the influenza virus: amantadine (SYMMETREL®) for the prophylaxis or treatment influenza A, rimantadine (FLUMADINE®) for prophylaxis or treatment influenza A in children, zanamivir (RELENZA®) for treatment of influenza A and B infection, and oseltamivir (TAMIFLU®) for treatment of influenza. None of the four antiviral agents has been demonstrated to be effective as a broad-spectrum anti-viral agent in preventing non-influenza viral infections or serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Worse still, the systemic application of these antiviral agents resulted in undesirable effects such as those related to CNS (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) and gastrointestinal tract irritation. Accordingly, there is a need for a safe, non-irritating and of broad-spectrum anti-viral composition, which comprise ingredients that are pharmaceutically acceptable and safe.
The common cold is one of the most frequently occurring human illnesses and is responsible for substantial morbidity. The common cold is believed to be caused by rhinoviruses (RVs), and to a less extent, adenovirus. Rhinoviruses are nonenveloped viruses that contain a single-strand ribonucleic acid (RNA) genome. RVs belong to the Picornaviridae family, which includes the genera Enterovirus (polioviruses, coxsackieviruses groups A and B, echoviruses, numbered enteroviruses) and Hepatovirus (hepatitis A virus). Approximately 101 serotypes are identified currently.
RV can be transmitted by aerosol or direct contact. Primary site of inoculation is the nasal mucosa, although the conjunctiva may be involved to a lesser extent. RV attaches to respiratory epithelium and spreads locally. The major human RV receptor is intercellular adhesion molecule-1 (ICAM-1), which is involved in the natural response of the human defense system to injury by, for example, aiding in the binding between endothelial cells and leukocytes. RV takes advantage of the ICAM-1 by using it as a receptor for attachment. In addition, RV uses ICAM-1 for subsequent viral uncoating during cell invasion. Some RV serotypes also up-regulate the ICAM-1 expression on human epithelial cells to increase infection susceptibility.
RV can directly cause or indirectly predispose an individual to a variety of upper respiratory tract infections (URTI) and lower respiratory tract infections (LRTI), which are less common.
Symptomatic treatment with analgesics, decongestants, antihistamines, and antitussives is currently the mainstay of therapy for RV-caused viral infections. Some clinicians advocate supplementation with vitamin C; however, high doses of vitamin C in children are not recommended. Zinc lozenges are not practical because of the metallic taste. The investigational agent, pleconaril (PICOVIR™), was found to be effective in inhibiting RV replication, but has not been approved for use. No effective drugs have been approved for the prophylaxis or treatment of the common cold.
The common viruses that are known to cause URT infections are listed in the table below:
Viruses That CauseViruses Causing Other Upperinfluenza-like illnessRespiratory Tract InfectionsInfluenzavirus ARhinovirusInfluenzavirus BAdenovirusCoronavirusParainfluenzavirusRespiratory Syncytial VirusOther Viruses
In addition to the types of viruses discussed above, other types of deadly viral diseases that are transmitted through sexual contact such as the genital herpes and herpes simplex, are also of great concern regarding to their treatment. These diseases are caused by viruses called herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2).
Herpes simplex viruses are complex by viral standards. They carry roughly 70,000 base pairs of double-stranded DNA. The DNA is enclosed within a capsid made of protein molecules, and the capsid is enclosed within an envelope made of a lipid bilayer. Protein molecules that help the virus bind to and infect certain types of cells project outwardly from the outer surface of the envelope. Those protein molecules are glycosylated, i.e., sugar molecules are attached to them, which makes it more difficult for an infected animal to generate an effective immune response to the virus.
Once contracted, genital herpes is incurable, and in addition to causing recurrent painful lesions, it poses a serious health threat. It can cause malignant transformation in animal and human cells, and has been linked to increased risks of cervical and vulvar cancer in women. The virus can also infect babies during birth, causing neonatal herpes, which is often fatal and can cause blindness, retardation, and other severe and permanent health problems if the baby survives.
Genital herpes is also believed to play an important role in the transmission of other sexually transmitted viruses, including acquired immunodeficiency syndrome (AIDS, which is caused by the human immunodeficiency virus, HIV). In effect, herpes lesions act as wounds or breaches in the protective layers of the skin and mucosal membranes, which provide vulnerable entry sites for invading viruses. If someone with genital herpes has intercourse with someone else who has HIV or some other sexually transmitted virus, the person with herpes is more likely than a non-herpetic individual would be to contract AIDS or another disease as a result. In addition, in people infected with both herpes and the HIV virus, herpes lesions presumably can increase the number of infectious HIV viral particles emitted by the infected person, since white blood cells infected by the HIV virus are likely to be present in the fluid in the herpes lesions. Therefore, any method for preventing the spread of genital herpes can help slow down the spread of AIDS and other sexually transmitted viruses.
The need for ways to reduce the spread of herpes and AIDS are especially acute. Despite intensive effort, there has been little progress in developing successful and effective prevention method.
In light of these problems confronting the prevention and the treatment of upper respiratory tract infections, sexually transmitted diseases, or other types of viral infections, it can be seen that a need exists in the art for a pharmaceutical composition that is generally characterized as safe, non-irritating and of broad-spectrum antiviral activities.